Benzophenone oxime ether compounds, pharmaceutical compositions and treatment methods

ABSTRACT

A new diphenyl-methane derivative is useful to inhibit agglomeration of blood and is defined by the formula, including a diphenylethylene derivative and a benzophenone oxime ether derivative. ##STR1## in which R1 and R2 each are hydrogen, hydroxyl or a lower alkoxy, U is ═CXY or ═N--O--W, 
     X is hydrogen, cyano or --COR6, R6 being hydroxyl or an amino, Y is --R10--COOR3, R3 being hydrogen or a lower alkoxy, R10 being an alkylene having 1 to 3 carbon atoms, straight or branched, --CO--NR4R5, R4 and R5 each being hydrogen, a lower alkyl or a lower arylalkyl, --CH2--NHSO2--C6H5 or --C(R8)═NR7, R7 being a lower alkoxy or an aryl, R8 is --VR9, V being oxygen, sulfur or nitrogen, R9 being an alkyl or an aryl, 
     W is --CH2--CO--CH2--COOR13, R13 being hydrogen or a lower alkyl, --CH2--C(═NOR14)--CH2--COOR15, R15 being hydrogen or a lower alkyl, R14 being a lower alkyl, --CH(CN)--(CH2)q--COOR16, R16 being hydrogen or a lower alkyl, q being an integer of 1 to 3, or --(CH2)p--Z, Z being --SH, --SCN or a monovalent group derived from a five- or six-membered ring which may be substituted by a ring having one or more sulfur atoms in the ring, p being 1 or 2.

This is a division of Ser. No. 07/364,712, filed June 9, 1989, now U.S.Pat. No. 4,954,523, which in turn is a division of Ser. No. 07/024,737,filed Mar. 11, 1987, now U.S. Pat. No. 4,886,834.

The invention relates to a diphenyl-methane derivative, a process forpreparing the same and the pharmaceutical use thereof. In particular, itrelates to a diphenylethylene derivative and a benzophenone oxime etherderivative.

The most serious diseases for mankind at present include acute vasculardiseases such as myocardial infarction, cerebral apoplexy, cerebralthrombosis, cerebral infarction, pulmonary embolus, deepphlebothrombosis and peripheral arteriothrombosis.

Recently antiplatelet agents have attracted public attention and beenclinically employed for treating these diseases. However theirapplication has been only lately realized. Thus it is expected todevelop better drugs in future.

The invention provides a diphenyl-methane derivative having the formula(XX) and a pharmacologically acceptable salt thereof: ##STR2## in whichR1 and R2 each are hydrogen, hydroxyl or a lower alkoxy, U is ═CXY or═N--O--W,

X is hydrogen, cyano or --COR6, R6 being hydroxyl or amino, Y is--R10--COOR3, R3 being hydrogen or a lower alkyl, R10 being an alkylenehaving 1 to 3 carbon atoms, straight or branched, --CO--NR4R5, R4 and R5each being hydrogen, a lower alkyl or a lower arylalkyl,--CH2--NHSO2--C6H5 or --C(R8)═NR7, R7 being a lower alkoxy or an aryl,R8 is --VR9, V being oxygen, sulfur or nitrogen, R9 being an alkyl or anaryl,

W is --CH2--CO--CH2--COOR13, R13 being hydrogen or a lower alkyl,--CH2--C(═NOR14)--CH2--COOR15, R15 being hydrogen or a lower alkyl, R14being a lower alkyl, --CH(CN)--(CH2)q--COOR16, R16 being hydrogen or alower alkyl, q being an integer of 1 to 3, or --(CH2)p--Z, Z being --SH,--SCN or a monovalent group derived from a five- or six-membered ringwhich may be substituted by a ring having one or more sulfur atoms inthe ring, p being 1 or 2.

In the formula (XX), R10 may be defined by --(CH2) n--in which n is 1, 2or 3.

The diphenyl-methane derivative as defined above includes twoembodiments. One is a diphenylmethane derivative having the formula (XX)in which U is ═CXY, also called a diphenylethylene derivative. The otheris a diphenyl-methane having the formula (XX) in which U is ═N--O--W,called a benzophenone oxime ether derivative The invention will beexplained in detail below in view of these two embodiments.

In addition, the invention provides a plurality of processes forpreparing the above defined diphenylmethane derivative. Each process isexplained below in detail.

Moreover the invention provides a pharmaceutical composition whichcomprises a pharmacologically effective amount of the diphenyl-methanederivative as defined above or a pharmacologically acceptable saltthereof and a pharmacologically acceptable carrier.

In this connection, the invention provides a method for treating adisease caused by the blood stream disorder with administration of thediphenylmethane derivative as defined above or a pharmacologicallyacceptable salt thereof.

The invention compound will be explained in more detail in line with theabove shown embodiments.

In one aspect of the invention, the desired compound of the presentinvention is a substituted diphenylethylene derivative of the generalformula (I) or a pharmaceutically acceptable salt thereof: ##STR3##wherein R¹ and R² may be the same or different from each other and eachrepresents a hydrogen atom, hydroxyl or a lower alkoxy group; Xrepresents a hydrogen atom, COR6 or a cyano group; wherein R6 ishydroxyl or amino and Y represents a group of the formula --(CH₂)_(n)--COOR³ (wherein R³ represents a hydrogen atom or a lower alkyl group;and n is an integer of 1 to 3), a group of the formula ##STR4## (whereinR⁴ and R⁵ may be the same or different from each other and eachrepresents a hydrogen atom or a lower alkyl or arylalkyl group) or agroup of the formula ##STR5## (wherein R²⁶ represents a hydrogen atom ora lower alkyl group), Y may be further --C(R8)═NR7.

In the above definition, a lower alkyl group as mentioned with regard toR³, R⁴ and R⁵ includes straight-chain or branched alkyl groups carryingone to six carbon atoms, e.g., methyl, ethyl, n-propyl, n-butyl,isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,1-ethylpropyl, isoamyl and n-hexyl groups. An alkoxy group as mentionedwith regard to R¹ and R² includes any lower alkoxy group derived fromthe lower alkyl groups as cited above. Among these groups, methyl andethyl groups are the most desirable lower alkyl groups while a methoxygroup is the most desirable lower alkoxy group.

An arylalkyl group as mentioned with regard to R⁴ and R⁵ includesbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl and phenethyl groups as well as heteroaryl groups suchas 2-picolyl, 3-picolyl and 4-picolyl groups.

A pharmaceutically acceptable salt of the aimed compound wherein R³ is ahydrogen atom includes metals salts such as Na, K, Ca and Mg salts.

PROCESS FOR PREPARATION

There may be various processes for preparing the compound (I) of thepresent invention. Typical examples thereof are as follows.

(1) The aimed compound of the formula (I), wherein Y is a group of theformula ##STR6## (wherein R⁴ and R⁵ may be the same or different fromeach other and each represents a hydrogen atom or a lower alkyl orarylalkyl group).

A carboxylic acid of the general formula (II): ##STR7## wherein R¹, R²and X are as defined above, or a reactive acid derivative thereof isconverted into an amide by reacting with an amine of the generalformula: ##STR8## wherein R⁴ and R⁵ are as defined above, to give acompound (I') which is one of the aimed compounds of the presentinvention: ##STR9## wherein R¹, R², X, R⁴ and R⁵ are as defined above.

A reactive acid derivative of the compound (III) includes, for example,a halide, an anhydride or a mixture of acid anhydrides of the compound(III). This reaction may be carried out in the presence of dehydratingagent(s) such as N,N'═dicyclohexylcarbodiimide,N,N'-diethylcarbodiimide, trialkyl phosphates, polyphosphate or tosylchloride, if required.

When a halide is used as a reactive derivative, base(s) may be added tothe reaction mixture to bind the hydrogen halide formed during thereaction, thus accelerating the reaction. Examples of the bases areinorganic salts such as potassium hydroxide, sodium hydroxide, potassiumcarbonate and sodium carbonate and tertiary amines such as pyridine andtriethylamine.

This reaction may be usually carried out in a solvent. Any solvent maybe employed so long as it exhibits no adverse effect on the reaction.Examples of such a solvent are dimethyl sulfoxide, tetrahydrofuran,dioxane, ethanol and mixtures thereof.

The reaction may be usually carried out at a temperature of -50° to 200°C. unless particularly limited. After the completion of the reaction,the aimed compound may be isolated in a conventional manner.

(2) The aimed compound of the formula (I), wherein Y is a group of theformula ##STR10##

An amine of the general formula (IV): ##STR11## wherein R¹, R² and X areas defined above, is reacted with a sulfonyl halide of the generalformula (V): ##STR12## wherein Hal represents a halogen atom, in aconventional manner to thereby readily give the aimed compound (I") inthe form of a sulfonamide: ##STR13##

This reaction may be usually carried out in a solvent. Any solvent maybe employed so long as it exhibits no adverse effect on the reaction.Examples of such a solvent are chloroform, 1,2-dichloroethane, ethylether, pyridine, tetrahydrofuran, dioxane, ethylene glycol dimethylether, benzene, toluene and mixtures thereof.

The temperature at which this reaction is carried out is notparticularly limited. Usually a temperature of -50° to 150° C. ispreferable. After the completion of the reaction, the aimed compound maybe isolated in a conventional manner.

(3) The aimed compound of the formula (I), wherein Y is a group of theformula --(CH₂)_(n) --COOR³ (wherein n and R³ are as defined above).

A ketone of the general formula (VI): ##STR14## wherein R¹ and R² are asdefined above, is reacted with a halide of the general formula (VII):##STR15## wherein Hal represents a halogen atom; and

n and R³ are as defined above,

for example, in the presence of zinc in tetrahydrofuran in aconventional manner to give a hydroxy compound of the formula (VIII)(Reformatsky's reaction). ##STR16##

Examples of the solvent available for the above reaction aretetrahydrofuran, benzene and ether. Further a solvent mixturecomprising, for example, trimethyl borate or triethyl borate withtetrahydrofuan may be employed.

This reaction may be usually carried out at a temperature ofapproximately -70° to 150° C.

The hydroxy compound (VIII) thus obtained may be dehydrated in aconventional manner to give a compound (I"') which is one of the aimedcompounds of the present invention. ##STR17##

Examples of the solvent available for this reaction are benzene,toluene, tetrahydrofuran, ether and dioxane, while examples of thecatalyst therefor are p-toluenesulfonic acid, thionyl chloride,phosphorus pentaoxide, iodine and hydrochloric acid. This reaction maybe carried out at a temperature of approximately -70° to 150° C.

The invention compound is defined to include a compound having theformula (I) in which Y is --C(R8)═NR7, that is, --C(VR9)═NR7, whichfalls within the scope of the first embodiment. R9 is an alkyl, asubstituted alkyl, an alkenyl or an aryl.

The compound is prepared by the below given procedures.

(7) A compound having the formula (I) in which Y is --CONHR7 is reactedwith a compound having the formula of HVR9 by a halogenating agent suchas phosphorus oxychloride, phosphorus pentachloride and thionyl chlorideto obtain a compound having the formula (I) in which Y is --C(VR9)═NR7,in a solvent such as benzene, toluene and chloroform. The reaction maybe effected in the presence of an organic base such as dimethylaniline,triethylamine and pyridine or an inorganic base such as potassiumcarbonate and sodium carbonate.

(8) The same starting compound as used in the preparation (7) is reactedwith a sulfurizing agent such as phosphorus pentasulfide in a solventsuch as benzene and toluene to obtain a corresponding thioamide havingthe formula (I) in which Y is --C(═S)--NH--R7. Then the thioamide isreacted with a halide having the formula of R9-hal to obtain a compoundhaving the formula (I) in which Y is --C(SR9)═NR7. A solvent and a basemay be used in the same way as shown in the preparation (7).

(9) A compound having the formula (I) in which Y is --C(VR9)═NR7, R9 isan alkyl or a substituted alkyl and R7 is a lower alkoxy is obtainedbelow. A compound having the formula (I) in which Y is --CO--VR9 isreacted with H2N--R7 to obtain the above intended compound.

The above shown procedures are illustrated below. ##STR18##

In Order to further illustrate the present invention, and not by way oflimitation, typical examples of the compound of the present inventionwill be given. Each compound will be shown in free form.

N-benzyl-3,3-bis(4-methoxyphenyl)acrylamide,

N-(2-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(3-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(4-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(2-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(3-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(4-methylbenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(2-methoxyphenyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(3-methoxybenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(4-methoxybenzyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(2-picolyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(3-picolyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-(4-picolyl)-3,3-bis(4-methoxyphenyl)acrylamide,

N-[3,3-bis(4-methoxyphenyl)allyl]benzenesulfonamide,

N-[3,3-bis(4-methoxyphenyl)allyl -p-toluenesulfonamide,

ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate,

4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid,

methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate,

ethyl 3-cyano-4,4-bis(4-methoxyphenyl)-3-butenoate,

ethyl 4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoate,

methyl 4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoate,

4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoic acid,

5-cyano-6,6-bis(4-ethoxyphenyl)-5-hexenoic acid, and

3-cyano-4,4-bis(4-ethoxyphenyl)-3-butenoic acid.

In addition to the compound species and the compounds obtained inExamples about the first embodiment of the invention, the followingcompounds are included within the scope of the invention.

N-phenyl-3,3-bis(4-methoxyphenyl)acrylamide in which the phenyl may besubstituted at 2, 3 or 4 position by chlorine.

N-(2-, 3- or 4-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide

N-(2-, 3- or 4-pyridyl)methyl-3,3-bis(4-methoxyphenyl)acrylamide

N-phenyl-N-methyl or isopropyl-3,3-bis(4-methoxyphenyl)acrylamide

N-(2-, 3- or 4-pyridyl)-N-methyl-3,3-bis(4-methoxyphenyl)acrylamide

N-(2-, 3- or 4-pyridyl)-N-isopropyl-3,3-bis(4-methoxyphenyl)acrylamide

N-(2-(N,N-dialkylamino)ethyl-3,3-bis(4-methoxyphenyl)acrylamide. thealkyl being methyl or ethyl.

N-(3-(N,N-dialkylamino)propyl-3,3-bis(4-methoxyphenyl)acrylamide, thealkyl being methyl or ethyl.

N,N-bis(2-(N,N-dimethylamino)ethyl)-3,3-bis(4-methoxyphenyl)acrylamide

N-(2-(N,N-dimethylamino)ethyl)-N-benzyl-3,3-bis(4-methoxyphenyl)acrylamide

N-phenyl-3,3-bis(4-ethoxyphenyl)acrylamide in which the phenyl may bereplaced by 2-chlorophenyl, 3-pyridyl, benzyl, 2-chlorobenzyl or(3-pyridyl)methyl.

N-phenyl-N-methyl-3,3-bis(4-ethoxyphenyl)acrylamide in which the phenylmay be replaced by 3-pyridyl or benzyl.

N-benzyl-N-isopropyl-3,3-bis(4-ethoxyphenyl)acrylamideN-(2-(N,N-dimethylamino)ethyl)-3,3-bis(4-ethoxyphenyl)acrylamide

N-(2-(N,N-diethylamino))ethyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-3,3-bis(4-ethoxyphenyl)acrylamide

N-benzyl-3,3-bis(4-hydroxyphenyl)acrylic amide

N-benzyl-3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)acrylic amide

N-benzyl-N-methyl-3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)acrylic amide

N-(2-(N,N-dimethylamino)ethyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)acryliamide

3,3-bis(4-methoxy, 4-ethoxy or 4-hydroxyphenyl)-N-phenyl-acrylic iminoacid ethyl ester

3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-N-phenylacrylic imino acid ethylester

3,3-bis(4-methoxyphenyl)-N-benzyl-acrylic imino acid ethyl ester

3,3-bis(4-methoxyphenyl)-N-(3-pyridyl)-acrylic imino acid methyl ester

3,3-bis(4-methoxy-, 4-ethoxy- or 4-hydroxy-phenyl)-N,N'-diphenylacrylicamidine

3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-N,N'-diphenylacrylic amidine

3,3-bis(4-methoxy- or 4-ethoxy-phenyl)-N,N'-dibenzylacrylic amidine

3,3-bis(4-methoxyphenyl)-N-phenyl-N'-benzylacrylic amidine

3,3-bis(4-methoxy-, 4-ethoxy- or 4-hydroxy-phenyl)-N-phenyl-acrylicthioimino acid allyl ester

3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)-N-phenylacrylic thioimino acidallyl ester

3,3-bis(4-methoxyphenyl)-N-benzyl-acrylic thioimino acid allyl ester

3,3-bis(4-methoxyphenyl)-N-(3-pyridyl)-acrylic thioimino acid ethylester

methyl 3-methoxyimino-5,5-bis(4-ethoxyphenyl)-4-pentenoate

3-methoxyimino-5,5-bis(4-methoxy- or 4-ethoxy-phenyl)-4-pentenoic acid

3-methoxyimino-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid

N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)methanesulfonic amide

N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)methanesulfonic amide

N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)benzenesulfonic amide

N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)benzenesulfonic amide

N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)beta-toluenesulfonicamide

N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)beta-toluenesulfonicamide

N-(3,3-bis(4-ethoxy- or 4-hydroxy-phenyl)allyl)-4-carboxybenzenesulfonicamide

N-(3-(4-methoxyphenyl)-3-(4-ethoxyphenyl)allyl)-4-carboxybenzenesulfonicamide

ethyl 3-cyano-4,4-bis(4-ethoxy- or 4-hydroxy-phenyl)-3-butenoate

ethyl 3-cyano-4-(4-methoxyphenyl)-4-(4-ethoxyphenyl)-3-butenoate

3-cyano-4,4-bis(4-methoxyphenyl)-3-butenoic acid

3-cyano-4,4-bis(4-hydroxyphenyl)-3-butenoic acid

3-cyano-4-(4-methoxyphenyl)-4-(4-ethoxyphenyl)-3-butenoic acid

ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate

ethyl 4-cyano-5,5-bis(4-hydroxyphenyl)-4-pentenoate

ethyl 4-cyano-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoate

ethyl 4-cyano-5-(4-hydroxyphenyl)-(Z)- or-(E)-5-(4-methoxyphenyl)-4-pentenoate

ethyl 4-cyano-5-(4-hydroxyphenyl)-(Z)- or-(E)-5-(4-ethoxyphenyl)-4-pentenoate,4-cyano-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid

ethyl 4-cyano-2-methyl-5,5-bis(4-methoxy-, 4-ethoxy-or4-hydroxy-phenyl)-4-pentenoate

ethyl4-cyano-2-methyl-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoate,4-cyano-2-methyl-5,5-bis(4-ethoxy-or 4-hydroxy-phenyl)-4-pentenoic acid

4-cyano-2-methyl-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid

methyl 5-cyano-6,6-bis(4-ethoxy- or 4-hydroxy-phenyl)-5-hexenoate

methyl 5-cyano-6-(4-methoxyphenyl)-6-(4-ethoxyphenyl)-5-hexenoate

5-cyano-6,6-bis(4-methoxy- or 4-hydroxy-phenyl)-5-hexenoic acid

5-cyano-6-(4-methoxyphenyl)-6-(4-ethoxyphenyl)-5-hexenoic acid

ethyl 4-ethoxycarbonyl-5,5-bis(4-methoxyphenyl)-4-pentenoate

4-carboxy-5,5-bis(4-ethoxy- or 4-hydroxy-phenyl)-4-pentenoic acid

4-carboxy-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid

ethyl 4-carbamoyl-5,5-bis(4-methoxyphenyl)-4-pentenoate

4-carbamoyl-5,5-bis(4-ethoxy- or 4-hydroxy-phenyl)-4-pentenoic acid

4-carbamoyl-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid

The aimed compound of the present invention is a substitutedbenzophenone oxime ether derivative of the general formula (I) or apharmaceutically acceptable salt thereof: ##STR19## wherein R¹ and R²may be the same or different from each other and each represents ahydrogen atom or a lower alkoxy group; and W represents a group of theformula ##STR20## (wherein R13 is a hydrogen atom or a lower alkylgroup), a group of the formula ##STR21## (wherein R¹⁵ represents ahydrogen atom or a lower alkyl group; and R¹⁴ represents a lower alkylgroup), a group of the formula ##STR22## (wherein R¹⁶ represents ahydrogen atom or a lower alkyl group; and q is an integer of 1 to 3) ora group of the formula --(CH ₂)_(p) --Z (wherein Z represents a group of

the formula --SH, a group of the formula --SCN or a monovalent groupderived from a five- or six-membered ring optionally substituted by aring having one or more sulfur atoms in the ring; and p is an integer of1 or 2).

In the above definition, a lower alkyl group as mentioned with regard toR¹³, R¹⁴, R¹⁵ and R¹⁶ includes straight-chain or branched alkyl groupscarrying one to six carbon atoms, e.g., methyl, ethyl, n-propyl,n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,1-ethylpropyl, isoamyl and n-hexyl groups. An alkoxy group as mentionedwith regard to R¹ and R² includes any lower alkoxy group derived fromthe lower alkyl groups as cited above. Among these groups, methyl andethyl groups are the most desirable lower alkyl groups while a methoxygroup is the most desirable lower alkoxy group.

A monovalent group derived from a five- or six-membered ring optionallysubstituted by a ring containing one or more sulfur atoms in the ring asmentioned with regard to Z of the compound (XI) of the inventionincludes, for example, 1-pyrrolyl, 1-(1,2,3,4-tetrazolyl),1-pyrrolidinyl, 1,3-dithianyl and 3-allylmercapto-1,2,4-triazolylgroups.

A pharmaceutically acceptable salt of the aimed compound of the formula(XI) in which R¹³, R¹⁵ and/or R¹⁶ are hydrogen atoms includes metalsalts such as Na, K, Ca and Mg salts.

Further some of the aimed compounds can be converted into acid additionsalts by reacting the same with a pharmaceutically acceptable inorganicor organic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic and sulfuric acids. Examples of such organicacids are maleic, fumaric, succinic, acetic, malonic, citric, benzoic,,oxalic and methanesulfonic acids. Process for Preparation

There may be various processes for preparing the compound (XI) of theinvention. Typical examples thereof are as follows.

Preparation process 4 ##STR23## wherein R¹, R² and W are as definedabove; and Hal represents a halogen atom.

Namely, a benzophenone compound of the formula (XII) is reacted with ahydroxylamine to give a benzophenone oxime of the formula (XIII) (Step1). Then the compound (XIII) is condensed with a halide of the formula(XIV) to give the aimed compound (XV) (Step 2). The obtained product maybe converted into a pharmaceutically acceptable salt in a conventionalmanner, if required.

Step 1 may be usually carried out at a temperature of approximately 0°to 200° C., preferably at room temperature to 100° C. with the use of asolvent such as methanol, ethanol, propanol, benzene, toluene or water.

Step 2 may be usually carried out at a temperature of approximately 0°to 100° C. with the use of a solvent such as dimethylformamide (DMF),dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, benzene ortoluene. The reaction may be carried out in the presence of a base suchas sodium hydride (NaH), triethylamine, dimethylaniline, potassiumhydroxide, methoxysodium (NaOMe), ethoxysodium (NaOEt) ortert-butoxypotassium to give a preferable result.

Preparation process 5

Aimed compound of the formula (XI) wherein R¹³, R¹⁵ and R¹⁶ in W arehydrogen atoms

An ester of the formula: ##STR24## wherein W' has the same meaning asthat of W in the general formula (XI) except that R¹³, R¹⁵, and R¹⁶ arehydrogen atoms, i.e., lower alkyl groups,

is hydrolyzed in a conventional manner, for example, with an alkali suchas caustic soda to give the aimed compound.

Preparation process 6

Aimed compound of the general formula (I) wherein W represents a groupof the formula ##STR25## represents a lower alkyl group; and R¹⁵represents a hydrogen atom or a lower alkyl group) ##STR26## wherein R¹,R², R¹⁴ and R¹⁵ are as defined above.

Namely, a compound of the general formula (XVI) is reacted with an amineof the general formula (XVII) to give a compound (XVIII) which is one ofthe aimed compounds. This reaction may be preferably carried out at atemperature of approximately -20° to 200° C. in a solvent such asmethanol, ethanol, propanol, benzene, toluene or water.

In order to further illustrate the present invention, and not by way oflimitation, typical examples of the compound of the present inventionwill be given. Each compound will be shown in free form.

4,4'-dimethoxybenzophenone 0-(3-methoxycarbonyl-2-oxopropyl)oxime,

4,4'-dimethoxybenzophenone 0-(3-ethoxycarbonyl-2- oxopropyl)oxime,

4,4'-dimethoxybenzophenone0-(3-methoxycarbonyl-2-methoxyiminopropyl)oxime,

4,4'-dimethoxybenzophenone0-(3-ethoxycarbonyl-2-methoxyiminopropyl)oxime,

4,4'-dimethoxybenzophenone 0-(3-carboxy-2-methoxyiminopropyl)oxime,

4,4'-dimethoxybenzophenone 0-(1-cyano-3-methoxycarbonylpropyl)oxime,

4,4'-dimethoxybenzophenone 0-(1-cyano-3-ethoxycarbonylpropyl)oxime,

4,4'-dimethoxybenzophenone 0-(1-cyano-3-carboxypropyl)oxime,

4,4'-dimethoxybenzophenone 0-(1-cyano-4-methoxycarbonylbutyl)oxime,

4,4'-dimethoxybenzophenone 0-(1-cyano-4-carboxybutyl)oxime,

4,4'-dimethoxybenzophenone0-{2-[3-allylmercapto-1,2,4-triazolyl)]ethyl}oxime,

4,4'-dimethoxybenzophenone 0-{2-[1-(1,2,3,4-tetrazolyl)]ethyl}oxime,

4,4'-dimethoxybenzophenone 0-{2-[2-(1,3-dithianyl)[ethyl}oxime,

4,4'-dimethoxybenzophenone 0-[2(1-pyrrolidinyl)ethyl]oxime,4,4'-dimethoxybenzophenone 0-(2-thiocyanatoethyl)oxime,

4,4'-dimethoxybenzophenone 0-(2-mercaptoethyl)oxime,

4,4'-dimethoxybenzophenone 0-[2-(1-pyrrolyl)ethyl]oxime,

4,4'-diethoxybenzophenone 0-(3-ethoxycarbonyl-2-oxopropyl)oxime,

4,4'-diethoxybenzophenone0-(3-ethoxycarbonyl-2-methoxyiminopropyl)oxime,

4,4'-diethoxybenzophenone 0-(3-carboxy-2-methoxyiminopropyl)oxime,

4,4'-diethoxybenzophenone 0-(1-cyano-3-ethoxycarbonylpropyl)oxime,

4,4'-diethoxybenzophenone 0-(1-cyano-3-carboxypropyl)oxime,

4-methoxybenzophenone 0-(3-ethoxycarbonyl-2-oxopropyl)oxime,

4-methoxybenzophenone 0-(3-ethoxycarbonyl-2-methoxyiminopropyl)oxime,

4-methoxybenzophenone 0-(3-carboxy-2-methoxyiminopropyl)oxime,

4-methoxybenzophenone 0-(1-cyano-3-ethoxycarbonylpropyl)oxime, and

4-methoxybenzophenone 0-(1-cyano-3-carboxypropyl)oxime.

The diphenyl-methane derivative of the invention, both diphenylenederivative and benzophenone oxime ether derivative, exhibits anexcellent effect in the pharmacological point of view. It effectivelyinhibits the aggulutination of platelets and eventually is useful for aremedy of an antiplatelet and antithrombotic agent. In particular, it isuseful for treating and/or preventing cerebrovascular diseases such astransient ischemic attack (TIA), cerebral infarction (thrombus andembolus) and cerebral arteriosclerosis; postoperative thrombus, embolusand blood stream disorders accompanying vascular operation andextracorporeal circulation; chronic arterial obstructions such asBuerger's disease, obstructive arteriosclerosis, peripheralarteriosclerosis, SLE and Raynaud's disease; and ischemic cardialdiseases such as stenocardia and myocardial infarction. It is furtheruseful for preventing recurrence of these diseases and for improvingprognosis thereof.

The effect of the invention product will be supported by the below givenpharmacological tests, first about the diphenylethylene derivative.

TEST EXAMPLE 1. Effect of inhibiting aggulutination of platelets (invitro)

The blood was collected from a human cubital vein in such a manner as tocontain a 3.8% solution of sodium citrate in an amount 1.10 time byvolume as much as the blood. Then platelet-rich plasma (PRP) wasprepared therefrom according to the method reported by Packham et al.(cf. Packham, M. A., et al, J. Exp. Med., 126, 171-189 (1967)). To 0.2ml of the obtained PRP, 25 μl portions of solutions of each compound ofthe present invention (A to E) at various concentrations were added andincubated at 37° C. for three minutes. Then the aggultination ofplatelets was induced with arachidonic acid, collage, ADP and PAF. Theaggulutination of platelets was evaluated according to the methodreported by Mustard et al. (cf. Mustard, J. F., at al., J. Lab. Clin.Med., 64, 548-559 (1964) with the use of an aggregometer available fromSchenko or Niko Bioscience Co. In other words, this test is carried outto examine the effect on platelet aggregation (in vitro).

Table 1 shows the result.

                                      TABLE 1                                     __________________________________________________________________________                  Effect of                                                              Effect of                                                                            inhibiting                                                                            Effect of                                                                            Effect of                                               inhibiting                                                                           arachidonic                                                                           inhibiting                                                                           inhibiting                                              collagen                                                                             acid    ADP    PAF                                                     agglutination                                                                        agglutination                                                                         agglutination                                                                        agglutination                                    Test Cpd.                                                                            IC.sub.50 (μM)                                                                    IC.sub.50 (μM)                                                                     IC.sub.50 (μM)                                                                    I C.sub.50 (μM)                               __________________________________________________________________________    Cpd. A 20     5       5      15                                               (Ex. 1)                                                                       Cpd. B 1.4    0.9     2.0    2.5                                              (Ex. 2)                                                                       Cpd. C 0.2    0.07    0.2    1.8                                              (Ex. 3)                                                                       Cpd. D 1.7    0.8     1.9    2.8                                              (Ex. 4)                                                                       Cpd. E 0.15   0.06    0.2    1.3                                              (Ex. 5)                                                                       __________________________________________________________________________     Note:                                                                         The compounds A to E as shown above corresponds to the aimed compounds        obtained in Examples 1 to 5, respectively.                               

2. Effect of inhibiting aggultination of platelets (ex vivo)

The compounds A to E, which were typical examples of the compound of thepresent invention, were orally administered to guinea pigs. After twohours, the blood of each animal was collected from the abdominal aortathereof under etherization. Then the effect of each compound on theaggultination of platelets induced by collagen (3 μg/ml) and arachidonicacid (50 μM) was examined. Table 2 shows the 50% effective dosesdetermined from the solvent administration ratios. In other words, thistest is conducted to examine the effect on platelet aggregation (exvivo).

                  TABLE 2                                                         ______________________________________                                                     Effect of  Effect of                                                          inhibiting inhibiting                                                         collagen   arachidonic acid                                                   agglutination                                                                            agglutination                                         Test Cpd.    ED.sub.50 (mg/kg)                                                                        ED.sub.50 (mg/kg)                                     ______________________________________                                        Cpd. A       100        100                                                   (Ex. 1)                                                                       Cpd. B       20         20                                                    (Ex. 2)                                                                       Cpd. C       0.05       0.03                                                  (Ex. 3)                                                                       Cpd. D       0.05       0.03                                                  (Ex. 4)                                                                       Cpd. E       1          0.3                                                   (Ex. 5)                                                                       Ticlopidine  ≦200                                                                              150                                                   ______________________________________                                    

3. Acute toxicity

The acute toxicities of the compounds A to E, which were typicalexamples of the compound of the present invention, were examined byadministering these compounds to male Wistar rats of 300 to 400 g inbody weight. As a result, the LD₅₀ of each compound was higher than 500mg per kg.

The effect of the invention will be supported also in view of thebenzophenone oxime ether derivative by the below given test data.

The test compounds L to R correspond to the products of Examples 11 to17, respectively.

The tests were conducted in the same way as shown before for thediphenylethylene derivative. Results for inhibition of aggulutinationare shown in Table 3 for the in-vitro test and in Table for the ex-vivotest. The acute toxicity test provided the same results as obtained withthe diphenylethylene derivative.

                                      TABLE 3                                     __________________________________________________________________________           Effect of                                                                            Effect of                                                                             Effect of                                                                            Effect of                                               inhibiting                                                                           inhibiting                                                                            inhibiting                                                                           inhibiting                                              collagen                                                                             arachidonic                                                                           ADP    PAF                                                     agglutination                                                                        agglutination                                                                         agglutination                                                                        agglutination                                    Test Cpd.                                                                            IC.sub.50 (μM)                                                                    IC.sub.50 (μM)                                                                     IC.sub.50 (μM)                                                                    IC.sub.50 (μM)                                __________________________________________________________________________    Cpd. L 0.5    0.1     0.8    1.2                                              (Ex. 11)                                                                      Cpd. M 14.0   12.5    13.2   20.0                                             (Ex. 12)                                                                      Cpd. N 2.8    0.7     5.0    4.1                                              (Ex. 13)                                                                      Cpd. O 14.0   7.0     20.0   14.5                                             (Ex. 14)                                                                      Cpd. P 1.1    0.4     2.7    1.5                                              (Ex. 15)                                                                      Cpd. Q 36.0   12.0    35.0   37.0                                             (Ex. 16)                                                                      Cpd. R 80.0   50.0    85.0   79.0                                             (Ex. 17)                                                                      __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                                     Effect of  Effect of                                                          inhibiting inhibiting                                                         collagen   arachidonic acid                                                   agglutination                                                                            agglutination                                         Test Cpd.    ED.sub.50 (mg/kg)                                                                        ED.sub.50 (mg/kg)                                     ______________________________________                                        Cpd. L       30         30                                                    (Ex. 11)                                                                      Cpd. M       55         55                                                    (Ex. 12)                                                                      Cpd. N       1.3        0.3                                                   (Ex. 13)                                                                      Cpd. O       1.0        0.3                                                   (Ex. 14)                                                                      Cpd. P       1.1        0.3                                                   (Ex. 15)                                                                      Cpd. Q       88         50                                                    (Ex. 16)                                                                      Cpd. R       ≦100                                                                              ≦100                                           (Ex. 17)                                                                      Ticlopidine  ≦200                                                                              150                                                   ______________________________________                                    

When the compound of the present invention is used as an antiplateletand antithrombotic agent, it may be orally or parenterally, for example,intramuscularly, subcutaneously or intravenously administered. The dosethereof may vary depending on, for example, the disease, the conditionand the age of each patient. Unless particularly limited, it may beadministered in a dose of 0.1 to 300 mg, preferably 0.1 to 60 mg,particularly preferably 0.3 to 30 mg, further particularly preferably0.6 to 10 mg to an adult per day.

The compound of the present invention may be formulated into, forexample, tablets, granules, powders, capsules, injections orsuppositories in conventional manners known in the art.

When it is to be formulated into solid preparations for oraladministration, excipients and, if required, other additives such asbinders, disintegrants, lubricants, colorants and corrigents are addedto the base and the obtained mixture is then formulated into, forexample, tablets, coated tablets, granules, powders or capsules inconventional manners.

Examples of the excipients are lactose, corn starch, white sugar,glucose, sorbitol and crystalline cellulose. Examples of the binders arepolyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gumarabic, tragacanth, gelatin, shellac, hydroxypropylcellulose,hydroxypropylstarch and polyvinylpyrrolidone. Examples of thedisintegrants are starch, agar, powdery gelatin, crystalline cellulose,calcium carbonate, calcium hydrogencarbonate, calcium citrate, dextrinand pectin. Examples of the lubricants are magnesium stearate, talc,polyethylene glycol, silica and hardened vegetable oils. Examples of thecolorants are those approved as additives for drugs. Examples of thecorrigents are cocoa powder, methol, aromatic acids, peppermint oil,Borneo camphor and cinnamon powder. These tablets and granules may be,as a matter of course, coated with, for example, sugar or gelatin ifrequired.

When an injection is to be prepared, various additives such as pHadjustors, buffers, stabilizers and preservatives are added to the baseand the obtained mixture is formulated into an injection forsubcutaneous, intramuscular or intravenous administration.

To further illustrate the present invention, and not by way oflimitation, the following Examples will be given.

EXAMPLE 1 N-Benzyl-3,3-bis(4-methoxyphenyl)acrylamide

2.84 g (0.01 M) of 3,3-bis(4-methoxyphenyl)acrylic acid was dissolved in10 ml of dimethylformamide. To the obtained solution, 1.2 g (0.012 M) oftriethylamine and 1.2 g of ethyl chlorocarbonate were added undericecooling. After one hour, 1.2 g of benzylamine was added thereto andthe mixture was stirred at room temperature for one hour. After thecompletion of the reaction, the reaction mixture was dissolved in 50 mlof ethyl acetate, washed with 10% hydrochloric acid, a saturated aqueoussolution of NaHCO₃ and a saline solution successively and dried overmagnesium sulfate followed by purifying by silica gel columnchromategraphy. Thus 3.3 g of the title compound having the followingphysicochemical properties was obtained.

m.p.: 99°-100° C.

NMR (CDCl₃)δ: 6.7-7.3(13H), 6.3(1H), 5.5(1H), 4.3(2H) and 3.8(6H).

EXAMPLE 2 N-[3,3-Bis(4-methoxyphenyl)allyl]benzensulfonamide

2.69 g of 3,3-bis-(4-methoxyphenyl)allylamine was dissolved in 5 ml ofpyridine. To the obtained solution, 1.9 g of benzenesulfonyl chloridewas added under icecooling and the mixture was stirred for five hours.After the completion of the reaction, the reaction mixture was dissolvedin ethyl acetate and washed with 5% hydrochloric acid and a saturatedsaline solution successively. The crude product thus obtained waspurified by silica gel chromatography in a conventional manner. Thus 3.6g of the title compound was obtained in the form of a colorless oilyproduct.

NMR (CDCl₃)δ: 7.8(2H), 7.5(3H), 6.7-7.1(8H), 5.8(1H), 4.4(1H), 3.8(6H),3.7(2H).

EXAMPLE 3 Ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate

2.42 g (0.01 M) of 4,4'-dimethoxybenzophenone, 1 g of zinc and 2.1 g oftrimethyl borate were suspended in 15 ml of tetrahydrofuran. To theobtained suspension, 2.2 g of ethyl 4-bromo-4-cyanobutyrate and acatalytic amount of iodine were added and the mixture was allowed toreact at room temperature for five hours. After the completion of thereaction, 10 ml of a saturated aqueous solution of ammonium chloride wasadded thereto and the mixture was stirred for one hour. After filteringthe zinc off, the filtrate was extracted with ethyl acetate. Theobtained crude product was purified by silica gel chromatography to give1.5 g of crystals. The crystals were dissolved in 10 ml of benzene and 1ml of thionyl chloride was added to the obtained solution. Afterstirring at room temperature for one hour, the reaction mixture wasconcentrated in vacuo and dispersed into ice/water. Then it wasextracted with benzene, washed with water and concentrated. Thus 1.3 gof the title compound was obtained in the form of a colorless oilyproduct.

NMR (CDCl₃)δ: 6.7-7.3(8H), 4.1(2H), 3.8(6H), 2.7(4H) and 1.3(3H).

EXAMPLE 4 4-Cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid

3.6 g of ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate wasdissolved in 10 ml of dioxane and 3 ml of a 5 N aqueous solution of NaOHwas added thereto. The obtained mixture was stirred at 60° C. for fivehours. After the completion of the reaction, the reaction mixture wasacidified and extracted with ethyl acetate. Thus 3.2 g of the titlecompound having the following physicochemical properties was obtained.This product could be further purified by recrystallizing from ethylacetate/hexane.

m.p.: 124°-125° C.

NMR (CDCl₃)δ: 9.5(1H), 6.8-7.4(8H), 3.8(6H), 2.7(4H).

EXAMPLE 5 Methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate

The procedure of Example 3 was followed except that the ethyl4-bromo-4-cyanobutyrate was replaced by 2.2 g of methyl5-bromo-5-cyanopentanoate. Thus the title compound having the followingphysicochemical properties was obtained.

NMR (CDCl₃)δ: 6.7-7.3(8H), 3.8(6H), 3.6(3H) and 1.8-2.6(6H).

EXAMPLES 6 to 13

6. N-phenyl-3,3-bis(4-methoxyphenyl)acrylamide

7. N-(3-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide

8. N-(4-pyridyl)-3,3-bis(4-methoxyphenyl)acrylamide

9. N-(2-chlorobenzyl)-3,3-bis(4-methoxyphenyl)acrylamide

10. N-(3-pyridyl)methyl-3,3-bis(4-methoxyphenyl)acrylamide

11. N-benzyl-N-methyl-3,3-bis(4-methoxyphenyl)acrylamide

12. N-benzyl-N-isopropyl-3,3-bis(4-methoxyphenyl)acrylamide

13.N-(2-(N,N-dimethylamino)ethyl)-N-(2-(3,4-dimethoxyphenyl)ethyl)-3,3-bis(4-methoxyphenyl)acrylamide

Each of the above listed compounds was obtained in the same way as shownin Example 1, except benzylamine was replaced by the respective, belowlisted compounds.

6. aniline, 7. 3-aminopyridine, 8. 4-aminopyridine, 9.2-chlorobenzylamine, 10. 3-aminomethylpyridine, 11. N-methylbenzylamine,12. N-isopropylbenzylamine, and 13.N,N-dimethyl-N'-(2-(3,4-dimethoxyphenyl)ethyl)ethylenediamine.

EXAMPLE 14 ethyl 3,3-bis(4-methoxyphenyl)-N-phenyl-acrylic imide

One gram (2.8 mmol) of the amide obtained in Example 6 was reacted with10 ml of phosphorus oxychloride at 60° C. for 2 hours. The productmixture was condensed and mixed with 50 ml of chloroform, 5 ml ofethanol and 5 ml of N,N-dimethylaniline, followed by further reaction at60° C. for 2 hours, to obtain 0.2 g of the above named compound.

EXAMPLE 15 3,3-bis(4-methoxyphenyl)-N,N'-diphenylacrylic amidine

This was obtained by reaction between 1 g of the amide obtained inExample 6 and 0.3 ml of aniline with 0.3 ml of phosphorus oxychloride in20 ml of toluene for 3 hours while refluxed. The amount was 80 mg.

EXAMPLE 16 allyl 3,3-bis(4-methoxyphenyl)-N-phenyl-acrylic thioimide

One gram of the amide obtained in Example 6 was reacted with 1.2 g ofphosphorus pentasulfide in 50 ml of benzene at 50° C. for 1 hour. Theproduct mixture was condensed and dissolved in chloroform, followed bywashing with water. 0.6 g of the thioamide was obtained from the productmixture with the chromatography using silicagel. 0.6 g (1.6 mmol) of thethioamide was reacted with 2.0 g (16 mmol) of allyl bromide with 0.5 gof potassium carbonate in 50 ml of tetrafurane at the room temperatureover one night. The reaction product mixture was condensed and dissolvedin chloroform, followed by washing with water. 0.45 g of the aboveintended compound was obtained with the chromatography of silicagel.

EXAMPLE 17 ethyl 3-methoxyimino-5,5-bis(4-methoxyphenyl)-4-pentenoate

4.0 g (11.3 mmol) of ethyl 3-oxy-5,5-bis(4-methoxyphenyl)-4-pentenoatewas reacted with 2.0g(24.0 mmol) of hydrochloric acid salt ofmethoxyamine in 50 ml of pyridine at 60° C. for 2 hours. 3.2 g of theabove intended compound was obtained.

EXAMPLE 18 3-methoxyimino-5,5-bis(4-methoxyphenyl)-4-pentenoic acid

2.0 g of the above intended compound was obtained by the same reactionas shown in Example 4 from the ester obtained in Example 17.

EXAMPLE 19 N-(3,3-bis(4-methoxyphenyl)allyl)-methanesulfonic amideEXAMPLE 20 N-(3,3-bis(4-methoxyphenyl)allyl)-4-carboxybenzenesulfonicamide

These were obtained by the same reaction as shown in Example 2, exceptthat methanesulfonic chloride and 4-(chlorosulfonyl)benzoic acid wererespectively used instead of benzenesulfonic chloride.

EXAMPLE 21

4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoic acid Example 3 was followedexcept for using 4,4'-diethoxybenzophenone and tetrahydrofurane as asolvent. The product mixture was dehydrated with thionyl chloride andhydrolyzed in the same way as shown in Example 4.

EXAMPLE 224-cyano-5-(4-hydroxyphenyl)-(Z)-5-(4-methoxyphenyl)-4-pentenoic acid andthe (E) compound thereof

Example 3 was followed except for using4-methoxy-4'-methoxymethoxybenzophenone. The product mixture was treatedwith hydrochloric acid and hydrolyzed in the same way as shown inExample 4. The elution of the product mixture with a mixture of methanoland chloroform at a ratio of 5:95 in the chromatography using silicagelprovided the (Z) compound. The elution with the mixture at a ratio of10:90 provided the (E) compound.

EXAMPLE 234-cyano-5-(4-hydroxyphenyl)-(Z)-5-(4-ethoxyphenyl)-4-pentenoic acid.

4-pentenoic acid and the (E) compound thereof Example 22 was followedexcept for using 4-ethoxy-4'-methoxymethoxybenzophenone.

EXAMPLE 24 4-cyano-5,5-bis(4-hydroxyphenyl)-4-pentenoic acid EXAMPLE 254-cyano-2-methyl-5,5-bis(4-methoxyphenyl)-4-pentenoic acid

Example 22 was followed except for using4,4'-dimethoxymethoxybenzophenone and 4,4'-dimethoxybenzophenone. Thehydrolysis product was the above intended compound.

EXAMPLE 26 4-carboxy-5,5-bis(4-methoxyphenyl)-4-pentenoic acid

Example 3 was followed except that diethyl 2-bromoglutarate was used forethyl 4-bromo-4-cyanobutyrate and the hydrolysis was conducted in thesame way as shown in Example 4.

EXAMPLE 27 4-carbamoyl-5,5-bis(4-methoxyphenyl)-4-pentenoic acid

Two grams of the acid obtained in Example 4 was heated with 10 ml of a 5N aqueous solution of NaOH in 50 ml of ethylene glycol at 150° C. for 12hours. The product mixture was acidified with hydrochloric acid andextracted with ethyl acetate. The extract was treated with thechromatography of silicagel to obtain 0.5 g of the above intendedcompound.

EXAMPLE 28

5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoic acid 260 mg of the esterobtained in Example 5 was treated in the same way as shown in Example 4to obtain 250 mg of the above intended compound.

The data of the NMR analysis about the compounds obtained in Examples 6to 28 is listed below. The analysis was conducted with CDCl₃, δ

    ______________________________________                                        examples     analysis                                                         ______________________________________                                         6           6.8-7.4(14H), 6.4(1H), 3.9(6H)                                    7           7.9-8.4(3H), 6.8-7.4(10H),                                                    6.4(1H), 3.8(6H)                                                  8           8.3(3H), 6.7-7.3(10H), 6.3(1H),                                               3.8(6H)                                                           9           7.0-7.3(8H), 6.7-6.9(4H), 6.3(1H),                                            5.7(1H), 4.4(2H), 3.8(6H)                                        10           8.5(1H), 8.3(1H), 7.0-7.5(6H),                                                6.8(4H), 6.3(1H), 5.6(1H),                                                    4.3(2H), 3.8(6H)                                                 11           6.7-7.4(13H), 6.3(1H), 4.5(2H),                                               3.8(6H), 2.7(3H)                                                 12           6.6-7.5(13H), 6.4(1H), 4.8(1H),                                               4.5(2H), 3.8(6H), 1.0(6H)                                        13           6.6-7.4(11H), 6.2(1H), 3.8(12H),                                              3.2-3.7(4H), 2.1-2.8(10H)                                        14           6.5-7.6(13H), 5.9(1H), 4.0(2H),                                               3.8(6H), 0.9(3H)                                                 15           6.6-7.4(19H), 6.1(1H), 3.8(6H)                                   16           6.5-7.3(13H), 6.2(1H), 5.8(1H),                                               5.1(2H), 3.5-3.8(8H)                                             17           6.7-7.3(8H), 6.6(1H), 4.0(2H),                                                3.9(3H), 3.8(6H), 2.9(2H), 1.2(3H)                               18           10.0(1H), 6.7-7.3(9H), 3.9(3H),                                               3.8(6H), 2.9(2H)                                                 19           6.6-7.4(8H), 5.9(1H), 4.4(1H),                                                3.8(8H), 2.9(3H)                                                 20           10.0(1H), 7.6-8.2(4H), 6.5-7.1(8H),                                           5.7(1H), 4.4(1H), 3.4-3.9(8H)                                    21           9.5(1H), 6.6-7.2(8H), 4.0(4H),                                                2.6(4H), 1.4(6H)                                                 22           8.0-9.5(2H), 7.1-7.5(2H),                                                     6.7-7.0(6H), 3.8(3H), 2.7(4H)                                    23           7.5-9.5(2H), 7.0-7.3(2H),                                                     6.6-6.9(6H), 4.0(2H), 2.6(4H),                                                1.4(3H)                                                          24           8.5-10.0(3H), 6.7-7.4(8H), 2.6(4H)                               25           9.0(1H), 7.1-7.3(2H), 6.6-7.0(6H),                                            3.8(6H), 2.3-3.1(3H), 1.2(3H)                                    26           8.0-9.5(2H), 6.7-7.4(8H),                                                     3.8(6H), 2.7(4H)                                                 27           8.2(1H), 6.6-7.2(10H), 3.7(6H),                                               2.3(4H)                                                          28           8.0-9.0(1H), 7.1-7.3(2H),                                                     6.7-7.0(6H), 3.8(6H),                                                         2.2-2.5(4H), 1.8-2.2(2H)                                         ______________________________________                                    

The above shown examples relate to the first group of the invention. Thesecond embodiment will be illustrated below.

EXAMPLE 294,4'-dimethoxybenzophenone-0-(3-ethoxycarbonyl-2-oxopropyl)oxime (1)Synthesis of 4,4'-dimethoxybenzophenone oxime

242 g (1 mole) of 4,4'-dimethoxybenzophenone was suspended in 2,000 mlof ethanol and 210 g (3 mole) of hydroxylamine hydrochloride and 300 ml(3 mole) of a 10 N aqueous solution of NaOH were added thereto. Then theobtained mixture was heated under reflux. After two or three hours, theethanol was distilled off in vacuo and then a saline solution was addedthereto followed by extracting with chloroform. The chloroform phase waswashed with water and dried over magnesium sulfate. After distilling thechloroform off, the residue was recrystallized from ethanol. Thus 240 gof the title compound was obtained in the form of colorless needles.

m.p.: 131° to 132° C.

NMR (CDCl₃)δ: 9.60 (b-s, 1H), 7.50 (m, 8H), 3.83 (s, 3H) 3.80 (s, 3H).

(2) Synthesis of 4,4'-dimethoxybenzophenone0-(3-ethoxy-carbonyl-2-oxopropyl)oxime

2.57 g (0.01 mol) of the 4,4'-dimethoxybenzophenone oxime as obtained in(1) was dissolved in 5 ml of dimethylformamide and 1.2 g of potassiumtert-butoxide was added thereto under ice cooling. The resulting mixturewas stirred for ten minutes. Then 1.8 g of ethyl 4-chloroacetoacetatewas added thereto and the obtained mixture was stirred at roomtemperature. After two hours, the reaction mixture was poured intodiluted hydrochloric acid and extracted with ethanol. The crude productthus obtained was purified by silica gel chromatography to give 3.1 g ofthe title compound.

NMR (CDCl₃)δ: 6.7-7.4(8H), 4.6(2H) 3.9-4.2(2H) 3.8(6H) 3.5(2H), 1.2(3H).

EXAMPLE 30 4,4'-Dimethoxybenzophenone0-(3ethoxycarbonyl-2-methoxyiminopropyl)oxime

3.85 g of the 4,4'-dimethoxybenzophenone0-(3-ethoxycarbonyl-2-oxopropyl)oxime as obtained in Example 1 wasdissolved in 5 ml of pyridine and 1 g of methoxylamine hydrochloride wasadded thereto. Then the obtained mixture was stirred at roomtemperature. After two hours, the reaction mixture was poured into ethylacetate, washed with diluted hydrochloric acid and then with a saturatedsaline solution and purified by silica gel chromatography. Thus 4 g ofthe title compound was obtained in the form of a colorless oily product.

NMR (CDCl₃)δ:

6.7-7.4(8H), 5.0, 4.7(2H), 3.8-4.2(2H) 3.8(9H) 3.3, 3.4(2H) 1.0-1.2(3H).

EXAMPLE 31 4,4'-Dimethoxybenzophenone0-(3-carboxy-2-methoxyiminopropyl)oxime

4.14 g of the 4,4'-dimethoxybenzophenone0-(3-ethoxycarbonyl-2-methoxyiminopropyl)oxime as obtained in Example 30was dissolved in 20 ml of methanol and 3 ml of a 5 N aqueous solution ofcaustic soda was added thereto. The obtained mixture was stirred at roomtemperature for five hours. After the completion of the reaction, thereaction mixture was acidified with diluted hydrochloric acid andextracted with ethyl acetate. Thus 3.8 g of the title compound wasobtained in the form of a colorless oily product.

NMR (CDCl₃)δ: 9.50(1H), 6.8-7.5(8H), 5.0, 6.8(2H), 3.8-3.9(9H), 3.5,3.3(2H).

EXAMPLE 31 4,4'-Dimethoxybenzophenone0-(1-cyano-3-ethoxycarbonylpropyl)oxime

The procedure of Example 29 was followed except that the ethyl4-chloroacetoacetate was replaced by 2.2 g of ethyl4-bromo-4-cyanobutyrate. Thus 3.6 g of the title compound having thefollowing properties was obtained.

NMR (CDCl₃)δ: 6.3-7.5(8H), 5.0(1H), 4.0-4.3(2H), 3.8(6H), 2.2-2.5(4H),1.2(3H).

EXAMPLE 33 4 4'-Dimethoxybenzophenone 0- (1-cyano-3-carboxypropyl)oxime

3.96 g of the 4,4'-dimethoxybenzophenone0-(1-cyano-3-ethoxycarbonylpropyl)oxime was dissolved in 20 ml ofdioxane and 3 ml of a 5 N aqueous solution of caustic soda was addedthereto. Then the mixture was allowed to react at 60° C. for five hours.After the completion of the reaction, the reaction mixture was acidifiedand extracted with ethyl acetate. Thus 3.6 g of the title compound wasobtained in the form of a colorless oily product.

NMR (CDCl₃)δ: 6.7-7.5(8H), 5.0(1H) 3.8(6H) 2.1-2.7(4H).

EXAMPLE 34 4,4'-Dimethoxybenzophenone0-(1-cyano-4-methoxycarbonylbutyl)oxime

The procedure of Example29 was followed except that the ethyl4-chloroacetoacetate was replaced by 2.2 g of methyl5-bromo-5-cyanopentanoate. Thus 3.7 g of the title compound of thefollowing properties was obtained.

NMR (CDCl₃)δ: 6.8-7.6(8H), 4.9(1H), 3.8(6H), 3.6(3H), 2.4(2H),1.6-2.2(4H).

EXAMPLE 35 4,4'-Dimethoxybenzophenone 0-(1-cyano-4-carboxybutyl)oxime

According to the procedure of Example 33, the title compound of thefollowing properties was obtained.

NMR (CDCl₃)δ: 6.7-7.5(8H), 4.9(1H), 3.8(6H), 2.4(2H), 1.5-2.2(4H).

What is claimed is:
 1. A substituted benzophenone oxime ether derivativehaving the formula ##STR27## wherein each of R¹ and R² is hydrogen,hydroxyl or lower alkoxy; Z is 3-allylmercapto-1,2,4-triazolyl,1-(1,2,4-tetrazolyl), 1,3-dithianyl, 1-pyrrolidinyl or 1-pyrrolyl; and pis an integer of 1 or 2, or pharmacologically acceptable salt thereof.2. A substituted benzophenone oxime ether derivative as set forth inclaim 1, wherein both of R¹ and R² are methoxy groups.
 3. A derivativeas claimed in claim 1, which is 4,4'-dimethoxybenzophenone0{2-[3-allylmercapto-1,2,4-triazolyl]ethyl}oxime.
 4. A derivative asclaimed in claim 1, which is 4,4'-dimethoxybenzophenone0{2-[1-(1,2,3,4-tetrazolyl)]ethyl}oxime.
 5. A derivative as claimed inclaim 1, which is 4,4'-dimethoxybenzophenone0-{2-[2-(1,3-dithianyl)]ethyl}oxime.
 6. A derivative as claimed in claim1, which is 4,4'-dimethoxybenzophenone0-[2-(1-pyrrolidinyl)]ethyl}oxime.
 7. A derivative as claimed in claim1, which is 4,4'-dimethoxybenzophenone 0-[2-(1-pyrrolyl)]ethyl}oxime. 8.A pharmaceutical composition which comprises a pharmacologicallyeffective amount of the substituted benzophenone oxime ether derivativeas defined in claim 1 or a pharmacologically acceptable salt thereof anda pharmacologically acceptable carrier.
 9. A method for treating apatient having a disease caused by aggregation of platelets or formationof thrombus which comprises administering to the patient atherapeutically effective amount of a pharmaceutical composition asclaimed in claim 27.